Postpartum depression (PPD) afflicts about 10-15% of pregnant women. Depression during pregnancy is the strongest risk factor for PPD. However, currently, significant confusion exists about whether treating depression during pregnancy could reduce the risk of PPD. Our preliminary studies suggest that treating prenatal depression may reduce PPD risk. To further determine (1) if prenatal depression itself increases the risk of PPD, thus should be treated, (2) if treatment is beneficial, and (3) which treatment is most effective i reducing PPD, we propose to conduct a two-stage prospective cohort study in Kaiser Permanente Northern California (KPNC). KPNC has implemented a unique universal peripartum depression screening program. All pregnant women (about 33,000 annually) are screened for depression twice during pregnancy and once postpartum using the Patient Health Questionnaire (PHQ-9). During the study period, 120,000 pregnant women who are screened for depression will be included in a peripartum depression screening registry. Using the information on depression status and treatment choices from all 120,000 women (stage-one sample), five cohorts will be formed: (A) Untreated cohort: those who screen positive for depression during pregnancy, but do not receive treatment; (B) Psychotherapy cohort: screen positive and receive psychotherapy only; (C) Antidepressant cohort: screen positive and use antidepressants only; (D) Combination treatments cohort: screen positive and use both psychotherapy and antidepressants; and (E) Control cohort: screen negative for depression and do not receive any treatments. For the stage-two sub-sample, we will randomly select 400 subjects from each of the five cohorts (a total of 2,000 women) and interview them in-person to obtain detailed information on confounders and effect modifiers for adjustment. Comparison of Cohort A versus Cohort E will determine if untreated depression in pregnancy increases the risk of PPD. Comparisons of Cohorts B, C, and D to Cohort A, respectively, will determine the effectiveness of depression treatment. Pair-wise comparisons among Cohorts B, C, and D will determine the comparative effectiveness of various treatment options including psychotherapy, anti-depressants, and combination therapies. Multiple linear regression analyses will be used to examine the treatment effectiveness in improving depression status from during to after pregnancy where within person change in PHQ-9 scores between prenatal and postpartum periods are compared. Logistic regression analyses will be used to examine the treatment effectiveness in reducing PPD risk where PPD risk (a dichotomized variable) is compared among all treatment groups. The findings will provide answers to pressing clinical questions of whether depression in pregnancy should be treated and, if so, which option is the best for reducing PPD. Selecting an effective treatment could lead to a reduction in PPD which remains a leading public health challenge worldwide. The established registry could be a valuable resource for many future studies of long-term effects of depression on maternal health and children's development.